Aerosolization is a desirable means for the delivery of therapeutic or diagnostic agents. Aerosol delivery avoids the problems associated with other delivery methods such as oral administration or injection. Injections are painful, present a risk of infection to the health-care provider from an inadvertent needle-stick, and create hazardous waste from the needle and syringe. Additionally, repeated injections can result in scarring. Oral administration must overcome several obstacles to the delivery of agents, including the acidic environment of the stomach, the ability of the agent to pass through the of the intestinal wall, and first-pass metabolism of the agent by the liver. Aerosol delivery, on the other hand, allows the direct delivery of agents to areas such as the nasal tract, the respiratory tract, or the eye, as well as systemic delivery into the circulation by administration to the respiratory tract and uptake into the circulation.
Prior methods of generating and delivering aerosols to the nasal and respiratory tract include metered-dose inhalers, dry powder inhalers and nebulizers. Prior methods of delivering agents to the eye include ointments and eyedrops. Administration of agents to the eye can lead to improper dosing due to blinking and drainage, and the squeamishness about inserting things into the eye can lead to problems with patient compliance.
Difficulties with prior methods of delivering aerosols include the inefficient use of materials being aerosolized, the lack of uniformity in the size of the particles generated, and the inability to direct the administered agent to a particular location within the respiratory tract. Additionally, metered-dose inhalers may use propellants which adversely affect the ozone layer.
A method of generating aerosols of defined particle size is therefore desirable in order to provide a more efficient and more controllable means of delivering therapeutic or diagnostic agents to a target tissue. A portable, reproducible means of providing such aerosols would also increase patient mobility and decrease health care expense by decreasing the need for expensive immobile equipment and monitoring costs associated with regulating the dosages received from inefficient devices.
Devices and methods for controlling aerosol particle size are known in the art. For example, U.S. Pat. No. 4,926,852 described control of particle size by metering a dose of medication into a flow-through chamber that has orifices to limit the flow rate. U.S. Pat. No. 4,677,975 described a nebulizer device having baffles to remove particles above a selected size from an aerosol. U.S. Pat. No. 3,658,059 employed a baffle that changes the size of an aperture in the passage of the suspension being inhaled to select the quantity and size of suspended particles delivered. U.S. Pat. No. 5,497,944 described a method and device for generating an aerosol by passing the formulation through a small nozzle aperture at high pressure. However, devices that process the aerosol particle size after generation (e.g., by filtering the aerosol after it is formed from the formulation) are typically inefficient, wasteful, and/or require a substantially greater amount of force to generate the aerosol.
Co-owned U.S. Pat. Nos. 5,544,646; 5,718,222; 5,660,166; 5,823,178 and 5,829,435 describe devices and methods useful in the generation of aerosols suitable for drug delivery. A drug formulation is forcibly applied to one side of the pore-containing membrane so as to produce an aerosol on the exit side of the membrane. Aerosols containing particles with a more uniform size distribution can be generated using such devices and methods, and can be delivered to particular locations within the respiratory tract.
Improved porous membranes for use in such devices would allow more efficient use of formulations, thereby requiring packaging of less formulation, and decreasing costs and increasing portability and patient compliance. These porous membranes can be of improved size, shape or arrangement. Thus there is a need for methods of producing nozzles for use in the aerosolization of diagnostic or therapeutic agents. There is a further need for aerosolization devices which are lightweight, portable and provide for precise aerosol particle size which can be targeted to a specific tissue.
We have now invented a method of forming nozzles of small, uniform size that permit the generation of uniform aerosols of diagnostic and therapeutic agents which can then be administered to particular target tissues such as the eye or specific areas of the respiratory tract. The method comprises directing a laser source onto a thin preferably flexible material so as to form pores substantially through the material. The pores may be formed either individually or simultaneously. The laser source may be controlled using a mask and/or beam-splitting or focusing techniques. In one embodiment, the pores are formed completely through the membrane. In another embodiment, the pores are formed so that a thin layer remains covering the exit side of the pore; this layer can then be burst outwards upon administration of a formulation at a pressure substantially below that which would rupture the remainder of the membrane. In another aspect of the invention, the pores are formed so as to have an entrance aperture that is larger than the exit aperture.
In one aspect of the invention, a neodymium-doped yttrium aluminum garnet (Nd:YAG) laser is used as the laser source. In another aspect of the invention, an excimer laser is used as the laser source. In still another aspect of the invention, the pores are formed so as to have an exit aperture of from about 0.5 to about 25 xcexcm in diameter.
In an additional aspect of the invention, a method of producing a nozzle for aerosolizing a formulation is provided wherein from about 200 to about 1,000 holes are formed in a membrane by projecting an excimer laser or focusing a YAG laser onto the membrane in a manner and for a time sufficient to ablate pores substantially through the membrane. In a particular embodiment, holes having an average relaxed exit aperture diameter of from about 0.5 to about 1.5 xcexcm and spaced from about 30 to about 70 xcexcm apart from each other can be formed in the membrane for the formation of particles for aerosol delivery to the respiratory tract.